The results of many studies indicate that estrogen replacement therapy (ERT) reduces the risk of coronary heart disease (CHD) in postmenopausal women. However, less than 9% of these women choose to take ERT because of unwanted side effects and concerns about increased risk of cancer associated with ERT. Therefore, alternative therapies are needed. The long-term objective of these studies is to evaluate a nutritional approach to ERT using ovariectomized monkeys as animal models of postmenopausal women. The isoflavonoids found in soy protein (specifically genistein) have many properties that may reduce the risk of CHD. These include favorable effects on plasma lipids and coronary artery vasomotion (see preliminary data). Furthermore, genistein is a tyrosine kinase (TK) inhibitor with inhibitory effects on thrombin activity and TK receptor-linked mitogens that may be associated with atherogenesis and neointimal formation after angioplasty. Therefore, studies are designed to examine the effects of ERT (in the form of conjugated estrogens [CEE]) and genistein on lipoprotein metabolism, coronary vasomotion, and arterial response to balloon injury. To better elucidate the vascular effects of CEE and genistein on vascular biology, studies will be done in normocholesterolemic, diet-induced dyslipoproteinemic-nonatherosclerotic, and dyslipoproteinemic-atherosclerotic monkeys.
The specific aims are to examine the effects of genistein and CEE on: 1) lipoprotein composition, arterial and hepatic LDL turnover (using radiolabeled LDL), messenger RNA levels for key proteins in lipid metabolism, and LDL oxidation in the plasma and arteries as they relate to atherogenesis, neointimal proliferation, and coronary vasomotion; 2) nitric oxide-mediated dilation (using specific agonists and antagonists coupled with arterial nitric oxide synthase expression) and endothelin- mediated constriction of large epicardial and smaller, resistance-size coronary arteries (using quantitative angiography and intravascular Doppler); and 3) neointimal formation (morphometry) and cellular proliferation (using BrDU) after balloon injury to the iliac artery, as modulated through arterial expression of platelet-derived growth factor (PDGF)-A, PDGF-B and alpha and beta receptor, and thrombin receptor.
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